CLAIMS
WHAT IS CLAIMED IS:
1. A process for preparing a hydroxy halide
alkylating agent or an organooxy halide alkylating
agent of formula (I):
<IMG>
(I)
wherein:
Q is selected from the following:
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
a C3-C14 carbocyclic ring system substituted
with 0-5 R31 or 0-5 R32;
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-2 R32;
R31 is selected independently from:
cyano, -CH2NR13R14, -NR13R14, -OR13, C2-C6
alkoxyalkyl, - S(O)mR13, -C(=O)NR13R14,
-81-
-NR14C (=O) R13, -NR14C (=O) OR14, -OC (=O) NR13R14,
-NR13C (=O) NR13R14, -NR13C (=S) NR13R14,
-NR14SO2NR13R14, -NR14SO2R13, -SO2NR13R14, C1-C4
alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, benzyl, phenethyl, phenoxy,
benzyloxy, nitro, C7-C10 arylalkyl, formyl, C3-C6
cycloalkoxy, C1-C4 alkyl substituted with
-NR13R14, C1-C4 alkoxycarbonyl, C1-C4
alkylcarbonyloxy, C1 -C4 alkylcarbonyl,
-OCH2CO2R13, 2- (1-morpholino) ethoxy, azido,
-C(R14) =N(OR14); or
1- 3 amino acids, linked together via amide
bonds, said amino acid being linked via the
amine or carboxylate terminus;
a C5-C14 carbocyclic residue substituted with
0-5 R32; or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-2 R32;
R32, when a substituent on carbon, is selected from
one or more of the following:
phenethyl, phenoxy, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, C7-C10 arylalkyl, benzyl
protected oxime, C2-C6 alkoxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkylcarbonyloxy, -NHSO2R14,
benzyloxy, 2- (1-morpholino)ethoxy, CONR13NR13R14,
cyano, sulfonamide, C3-C6 cycloalkoxy, NR13R14
-82-
-C(R14)=N(OR14), -NO2, -OR13, -NR40R41, -SR13,
-SOR13, -SO2R13, -SNR13R14, SONR13R14,
-SO2NR13R14, -C(=O)NR13R14, OC(=O)NR13R14,
-C(=O)R11, phenyl, -C(=O)NR13- (C1-C4 alkyl) -
NR13R14, -C (=O) NR40R41,
-C(=O) NR13C (R11) 2NR13R14;
-C(=O)NR13C(R11)2NR13CO2R13;
-C(=O)NR13- (C1-C4 alkyl) -NR13CO2R13;
-C(=O)N(R13) - (C1-C4 alkyl) -R11; or
-C (=O) C (R1) 2NR13R14;
-C(=O) C(R11) 2NR13CO2R13; -C(=O) - (C1-C4 alkyl) -
NR13R14; -C(=O) - (C1-C4 alkyl) -NR13CO2R13; or
C1-C4 alkoxy substituted with 0 - 4 groups selected
from: R11, C3-C6 cycloalkyl, - CO2R13,
-C(=O)NR13R14, -NR13R14 or OH;
C1-C4 alkyl substituted with 0 - 4 groups selected
from: R11, =NR14, =NNR13C(=O)NR13R14,
=NNR13C (=O) OR13, or -NR13R14;
C2 - C4 alkenyl substituted with 0 - 4 R11;
C2 - C4 alkynyl substituted with 0 - 4 R11;
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected
from oxygen, nitrogen or sulfur, substituted with
0-2 R12;
or R32 may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5- or
6-membered ring, said 5- or 6- membered ring being
-83-
optionally substituted on the aliphatic carbons
with halogen, C1-C4 alkyl, C1-C4 alkoxy,
benzyloxy, or
-NR13R14; or, when R32 is attached to a saturated
carbon atom, it may be =O, =S, =NO-benzyl; or when
R32 attached to sulfur it may be =O;
R32, when a substituent on nitrogen, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, benzyloxy, C1 - C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4
alkylcarbonyl, -C(R14)=N(OR14);
R40 is selected from: H, C1-C3 alkyl;
R41 is selected from:
-C (=O)NR13R14;
-C (=O)NR13NR13R14;
-C (=O)C(R11)2NR13R14;
-C (=O)C(R11)2NR13NR13R14;
-C (=O)C(R11)2NR13CO2R13;
-C (=O)H;
-C (=O)R11;
-C (=O)-(C1 - C4 alkyl)-NR13R14;
-C (=O)-(C1 - C4 alkyl)-NR13CO2R13;
1- 3 amino acids linked together via amide bonds,
and linked to the N atom via the
carboxylate terminus;
R11 is selected from one or more of the following:
H, keto, cyano, -CH2NR13R14, -NR13R14, -OR13
-S (O) mR13, -NR14C (=O) R13, =NOR14
-84-
-NR14C(=O)OR14, -OC(=O)NR13R14,
-NR13C (=O) NR13R14, -NR14SO2NR13R14, NR14SO2R13,
-SO2NR13R14, -OP(O) (OR13)2, C1-C4 alkyl, C2-C4
alkenyl, C3 - C6 cycloalkylmethyl, benzyl,
phenethyl, phenoxy, benzyloxy, nitro, C7-C10
arylalkyl, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl
substituted with -NR13R14, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkylcarbonyl, C1 - C4 alkylcarbonylamino,
2- (1-morpholino) ethoxy, azido, or
-C (R14) =N(OR14);
1 - 3 amino acids linked together via amide bonds,
said amino acid being linked via the amine or
carboxylate terminus;
C3-C10 cycloalkyl substituted with 0-2 R12;
C1-C4 alkyl substitued with 0-2 R12
aryl(C1-C3 alkyl)-, substituted with 0-2 R12;
C2 - C6 alkoxyalkyl -, substituted with 0 - 2 R12;
C1-C4 alkylcarbonyloxy substituted with 0-2 R12,
C6 - C10 arylcarbonyloxy substituted with 0 - 2 R12,
a C5 - C14 carbocyclic residue substituted with 0 -
3 R12;
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
-85-
heterocyclic ring system being substituted with
0-3 R12;
R11A is selected from one or more of the following:
H, keto, cyano, -CH2N(R13A)R(14A), N(R13A)R(14A,
-CO2H, -OC(=O) (C1-C3 alkyl), -Obenzyl, C2-C6
alkoxyalkyl, -C(=O)NH2, -OC(=O)NH2, C1-C4 alkyl,
C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, benzyl, phenethyl, phenoxy,
benzyloxy, nitro, C7-C10 arylalhyl, C3-C6
cycloalkoxy, C1-C4 alkyl, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, C1-C4 alkylcarbonylamino,
2- (1-morpholino)ethoxy, azido, aryl(C1-C3 alkyl),
a C5-C14 carbocyclic residue; a 5- to 10-
membered heterocyclic ring system containing 1
to 4 heteroatoms independently selected from
oxygen, nitrogen or sulfur, said heterocyclic
ring system substituted with 0-3 R12A;
R12, when a substituent on carbon, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3 - C6 cycloalkylmethyl, C7-C10
arylalkyl, C1 - C4 alhoxy, sulfonamide, formyl, C3 - C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkylene optionally
substituted with -Si (CH3) 3, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, C1-C4 alkylcarbonylamino, -SR13,
-86-
-SOR13, - SO2R13, -SO2NR13R14, -NHSO2R14
-OCH2CO2R13, 2- (1-morpholino)ethoxy,
-C(R14)=N(OR14); or
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected from
oxygen, nitrogen or sulfur;
or R12 may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5 - or
6-membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons
with C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14; or, when R12 is attached to a saturated
carbon atom, it may be =O or =S; or when R12 is
attached to sulfur it may be =O;
R12, when a substituent on nitrogen, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, benzyloxy, C1-C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4
alkylcarbonyl, -C(R14)=N(OR14);
R12A, when a substituent on carbon, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
nitro, cyano, C1 - C4 alkyl, C3 - C6 cycloalkyl, C3 - C6
cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy,
sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C2-
C6 alkoxyalkyl optionally substituted with
-Si (CH3) 3, C1-C4 benzyloxyalkyl, methylenedioxy,
- 87 -
ethylenedioxy, C1-C4 alkylcarbonyl, C1-C4
alkylcarbonylamino, -SMe, -S(=O)Me, -SO2Me,
-OCH2CO2R13, 2-(1-morpholino)ethoxy; or
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected from
oxygen, nitrogen or sulfur;
or R12A may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5- or
6-membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons
with C1-C4 alkyl, C1-C4 alkoxy, benzyloxy; or, when
R12A is attached to a saturated carbon atom, it may
be =O or =S; or when R12 is attached to sulfur it
may be =O;
R12A, when a substituent on nitrogen, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, benzyloxy, C1-C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6
alkoxyalkyl, C1-C4 alkylcarbonyl;
R13 is selected from:
phenyl substituted with 0-3 R11A;
benzyl substituted with 0-3 R11A;
C1-C6 alkyl substituted with 0-3 R11A;
C2-C4 alkenyl substituted with 0-3 R11A;
C1-C6 alkylcarbonyl substituted with 0-3 R11A;
C1-C6 alkoxycarbonyl substituted with 0-3 R11A;
C1-C6 alkylaminocarbonyl substituted with 0-3
R11A;
C3-C6 alkoxyalkyl substituted with 0-3 R11A;
-88-
an amine protecting group when R13 is bonded to
N;
a hydroxy protecting group when R13 is bonded to
O;
R14 is benzyloxy, C1-C6 alkyl substituted with 0-3
groups selected from - Obenzyl, C1-C4 alkoxy, C1-
C6 alkoxy, C2-C6 alkenyl, phenyl, benzyl, an
amine protecting group when R14 is bonded to N, a
hydroxy protecting group when R14 is bonded to O;
R13 and R14 can alternatively join to form - (CH2)4-,
-(CH2)5-, -CH2CH2N(R15)CH2CH2-, or
-CH2CH2OCH2CH2-;
R13A and R14A are independently selected from: H, C1-
C6 alkyl;
R13A and R14A can alternatively join to form -(CH2)4-,
-(CH2) 5-, -CH2CH2N(R15)CH2CH2-, or
- CH2CH2OCH2CH2-;
R15 is H or CH3;
X is chloro, bromo or iodo,
R3 is a hydroxy protecting group; and
m and n are independently 1, 2 or 3;
said process comprising the steps of:
(1) reacting an organodiol of formula (II):
- 89 -
<IMG>
(II)
wherein Q, m and n are as aefined above for formula
(I), with a halogenating reagent in a chlorinated
organic solvent, with the proviso that the
halogenating reagent is not a hydrogen halide, to form
a compound of formula (IA):
<IMG>
(IA)
wherein Q, X, m, and n are as defined above for
formula (I); and
(2) reacting compound (IA) with a reagent
suitable for the protection of hydroxy groups to form
the compound of formula (I) wherein R3 is a hydroxy
protecting group.
2. A process of Claim 1 for preparing an
alkylating agent compound of formula (I) wherein:
Q is selected from:
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
a C3-C14 carbocyclic ring system substituted
with 0-5 R31 or 0-5 R32;
- 90 -
R31 is selected from one or more of the following:
cyano, -CH2NR13R14, -NR13R14, -OR13, C2-C6
alkoxyalkyl, -SR13, -SOR13, -SO2R13, C1-C4
alkyl, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, benzyl, phenethyl, phenoxy,
benzyloxy, nitro, C7-C10 arylalkyl, formyl, C3-C6
cycloalkoxy, C1-C4 alkyl substituted with
-NR13R14, C1-C4 alkoxycarbonyl, C1-C4
alkylcarbonyloxy, C1-C4 alkylcarbonyl,
-OCH2CO2R13, 2- (1-morpholino) ethoxy, azido,
-C(R14)=N(OR14); or
a C5-C14 carbocyclic residue substituted with
0-5 R32; or
aryl substituted with 0-3 R32; or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-2 R32;
R32, when a substituent on carbon, is selected from
one or more of the following:
phenethyl, phenoxy, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, C7-C10 arylalkyl, benzyl
protected oxime, C2-C6 alkoxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkylcarbonyloxy, -NHSO2R14,
benzyloxy, 2-(1-morpholino) ethoxy, -CONR13NR13R14,
cyano, sulfonamide, C3-C6 cycloalkoxy, -NR13R14,
- 91 -
-C(R14)=N(OR14), -NO2, -OR13, -NR40R41, -SOpR13,
-SNR13R14, -SONR13R14, -SO2NR13R14, C(=O)NR13R14,
-OC(=O)NR13R14, -C(=O)R11, phenyl, -C(=O)NR13- (C1-
C4 alkyl) -NR13R14, -C (=O) NR40R41;
-C (=O) NR13C (R11) 2NR13R14;
-C (=O)NR13C(R11)2NR13CO2R13;
-C (=O)NR13- (C1-C4 alkyl) -NR13CO2R13;
-C (=O)N(R13) - (C1-C4 alkyl) -R11; or
-C (=O)C(R11)2NR13R14;
-C (=O)C(R11)2NR13CO2R13; -C(=O) - (C1-C4 alkyl) -
NR13R14; -C (=O) - (C1-C4 alkyl) -NR13CO2R13; or
C1-C4 alkoxy substituted with 0-4 groups selected
from: R11, C3-C6 cycloalkyl, -CO2R13,
-C(=O)NR13R14, -NR13R14 or benzyloxy;
C1-C4 alkyl substituted with 0-4 groups selected
from: R11, =NR14, =NNR13C(=O)NR13R14, or NR13R14;
C2-C4 alkenyl substituted with 0-4 R11;
C2-C4 alkynyl substituted with 0-4 R11;
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected
from oxygen, nitrogen or sulfur, substituted with
0-2 R12;
or R32 may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5- or
6-membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons
with halogen, C1-C4 alkyl, C1-C4 alkoxy,
- 92 -
benzyloxy, or -NR13R14; or, when R32 is attached
to a saturated carbon atom, it may be =O, =S, =NO-
benzyl; or when R32 attached to sulfur it may be
=O;
R32, when a substituent on nitrogen, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, benzyloxy, C1-C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4
alkylcarboyl, - C(R14) =N (OR14);
R40 is selected from: H, C1-C3 alkyl;
R41 is selected from:
- C (=O) NR13R14;
- C (=O) NR13NR13R14;
- C (=O) C (R11) 2NR13R14;
- C (=O) C (R11)2NR13NR13R14;
- C (=O) C (R11) 2NR13CO2R13;
- C (=O) H;
- C (=O) R11;
- C (=O) - (C1-C4 alkyl) - NR13R14;
- C (=O) - (C1-C4 alkyl) -NR13CO2R13;
1 - 3 amino acids linked together via amide bonds,
and linked to the N atom via the carboxylate
terminus;
R11 is selected from one or more of the following:
H, keto, cyano, -CH2NR13R14, -NR13R14, -OR13
-SR13, -SOR13, -SO2R23, C1-C4 alkyl, C2-C4
- 93 -
alkenyl, C3-C10 cycloalkyl substituted with 0-2
R12, a C5-C14 carbocyclic residue substituted
with 0-3 R12, aryl(C1-C3 alkyl)-, substituted
with 0-2 R12, aryl substituted with 0-3 R12; or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-3 R12;
R12, when a substituent on carbon, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10
arylalkyl, C1-C4 alkoxy, sulfonamide, formyl, C3-C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkyl optionally
substituted with -Si(CH3)3, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, C1-C4 alkylcarbonylamino, -SR13,
-SOR13, -SO2R13, SO2NR13R14, -NHSO2R14,
2-(1-morpholino)ethoxy, -C(R14)=N(OR14); or
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected from
oxygen, nitrogen or sulfur;
or R12 may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5 - or
6-membered ring, said 5- or 6- membered ring being
-94-
optionally substituted on the aliphatic carbons
with C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14; or, when R12 is attached to a saturated
carbon atom, it may be =O or =S; or when R12 is
attached to sulfur it may be =O;
R12, when a substituent on nitrogen, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, benzyloxy, C1 - C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3 - C6 cycloalkylmethyl, - CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4
alkylcarbonyl, - C(R14) =N (OR14);
R13 is C1-C6 alkyl; C3-C6 alkoxyalkyl; C2-C4 alkenyl;
phenyl; or benzyl;
R14 is benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6
alkenyl, phenyl, benzyl, an amine protecting
group when R14 is bonded to N, or a hydroxy
protecting group when R14 is bonded to O;
R15 is H or CH3;
X is chloro, bromo or iodo;
R3 is a hydroxy protecting group;
m and n are independently 1, 2 or 3.
3. A process of Claim 1 wherein:
Q is selected from:
-95-
allyl, methyl, ethyl, propyl, cyclopropylmethyl,
n-butyl, i-butyl, CH2CH=C(CH3)2,
pyridinylmethyl, methallyl, n-pentyl, i-pentyl,
hexyl, phenyl, isoprenyl, progargyl, picolinyl,
methoxyethyl, cyclohexylmethyl, dimethyl-butyl,
ethoxyethyl, methyl-oxazolinylmethyl,
naphthylmethyl, methyloxazolinylmethyl,
vinyloxyethyl, pentafluorophenyl,
quinolinylmethyl, carboxyphenyl,
benzyloxyphenyl, phenylphenyl, adamantylethyl,
cyclopropylmethoxyphenyl, methoxyphenyl,
methylphenyl, ethoxyphenyl,
benzyloxymethylphenyl, N-protected aminophenyl,
formylphenyl, cyanophenyl, cinnamyl,
allyloxyphenyl, fluorophenyl, difluorophenyl,
fluoromethylphenyl, cyclobutylmethyl,
cyclopentylmethyl, nitrophenyl, (H2NC(=O)) -
phenyl, carbomethoxyphenyl, carboethoxyphenyl,
tetrazolylphenyl, and dimethylallyl, N-protected
aminomethylphenyl, (O-benzyl-
formaldoxime)phenyl, (O-methyl-
formaldoxime)phenyl, (CH3O2CO)-phenyl, (benzyl-
OCH2CH2N=CH) -phenyl,
N-benzylaminocarbonylphenyl, N-protected N-
methylaminophenyl, N-protected
N-ethylaminophenyl, N-protectea
N-ethylaminomethylphenyl, acetylphenyl,
acetoxyphenyl, N-benzyloxylaminophenyl,
N-benzyloxylaminomethylphenyl,
(benzyloxyl) ethylphenyl, (CH3C(=NO-benzyl))-
phenyl, (H2NNHC(=O) ) -phenyl, (H2NC(=O)NHN=CH) -
phenyl, (CH3ONHC(=O) ) -phenyl, (HONHC(=O) ) -
phenyl, (CH3NHC(=O) ) -phenyl,
N,N-dimethylaminocarbonylphenyl, (benzyl-
- 96 -
OCH2CH(OH)CH2O)-phenyl, benzyloxyethoxyphenyl,
(oxazolidinyl) -phenyl, (benzyloxyl) hexyl,
hexenyl, (benzyloxy) octyl, (benzyloxyl) pentyl,
(carboxy) pentyl, (carbomethoxy) pentyl,
(methylthio)phenyl, (methylsulfonyl)phenyl,
N,N-dimethylaminomethylphenyl, N-protected
N-methylaminomethylphenyl, glycylaminophenyl,
N,N-dimethylglycylaminophenyl,
alanylaminophenyl, (N-
phenylmethoxycarbonyl) alanylaminophenyl,
phenylalanylaminophenyl, (N-
phenylmethoxycarbonyl) phenylalanylaminophenyl,
(CH3CH2NHC(=O) ) -phenyl, N,N-
diethylaminocarbonylphenyl,
N-ethylaminocarbonylphenyl,
N-propylaminocarbonylphenyl,
N,N-diisopropylaminocarbonylphenyl, N,N-di-n-
propylaminocarbonylphenyl,
(benzyloxypropynyl) phenyl, (imidazolyl-C (=O) ) -
phenyl, (pyrazolyl-C(=O) ) -phenyl,
(pyridylmethylaminocarbonyl) phenyl,
(oxadiazolidinonyl)phenyl,
trifluoroacetylphenyl, (pyrazolyl) phenyl,
(H2NSO2)-phenyl, dibenzyloxyethylphenyl,
(NeHNC(=O)NH)-phenyl, (H2NC(=O)NH)-phenyl,
(HC (=O) NH) -phenyl, methanesulfonylpentyl,
methoxypentyl, N-formyl -N-methylaminophenyl,
acetylaminophenyl, propionylphenyl,
butyrylphenyl, (CH3CH2C (=NObenzyl) ) -phenyl,
(trifluorohydroxyethyl) phenyl, (CF3C (=NOH) ) -
phenyl, (N-methylglycyl) aminophenyl,
((4-morpholino) ethyl) aminocarbonylphenyl,
(N,N-dimethylaminoethyl) aminocarbonylphenyl,
(N,N-diethylaminoethyl) aminocarbonylphenyl,
(4-methylpiperazin- 1 -
- 97 -
ylethyl) aminocarbonylphenyl, (benzyl-
NHC (=O) O) phenyl, (CH3NHC (=O) O) phenyl,
(NH2C (=O) CH2O) phenyl, (NH2C (=NH)) phenyl,
((N-phenylmethoxycarbonyl) glycylamino) phenyl,
(imidazolylmethyl) phenyl, ((CH3) 3C-C (=O)) phenyl,
(N-methyl - N-ethylaminoethyl) aminocarbonylphenyl,
(pyrrolidinylethyl)aminocarbonylphenyl,
(piperidinylethyl) aminocarbonylphenyl,
(H2NC(=NObenzyl))phenyl,
(H2NC(=NObenzyl)) fluorophenyl,
benzimidazolylmethyl, benzotriazolylmethyl,
indazolylmethyl, benzoxazolinylmethyl,
benzisoxazolylmethyl, thienylmethyl, or
furylmethyl;
m and n are independently 1, 2 or 3;
X is chloro, bromo or iodo;
R3 is a hydroxy protecting group.
4. A process of Claim 1 for preparing an
alkylating agent compound of formula (I) wherein:
Q is selected from:
allyl, propyl, cyclopropylmethyl, n-hexyl,
n-butyl, CH2CH=C(CH3) 2, methallyl, i-pentyl,
phenyl, hexyl, isoprenyl, cinnamyl,
fluorophenyl, (methylsulfonyl)phenyl
cyclopropylmethyl, naphthylmethyl,
4-pyridinylmethyl, 2-pyridinylmethyl,
carboxypentyl, cyclopentylmethyl, cyanophenyl,
quinolinylmethyl, vinylphenyl, methylphenyl,
- 98 -
carbomethoxyphenyl, formylphenyl, (O-benzyl-
formaldoxime)phenyl, cyclobutylmethyl,
difluorophenyl, nitrophenyl, N-protected
aminomethylphenyl, 3-(NHCHO)phenyl,
benzyloxyphenyl, N-benzyloxylaminomethylphenyl,
3-(CH3OC(=O)O-)phenyl, 3-(1-
benzyloxyethyl)phenyl, 3-(HOCH2CH2N=CH)phenyl,
3-(2-oxazolidinyl)phenyl, 3-
(C6H5CH2NHC(=O)O)phenyl, 3-(CH3NHC(=O)O)phenyl,
acetylphenyl, (CH3C(=NO-benzyl))-phenyl, 2-
(hydroxymethyl)-cyclopropylmethyl, (H2NNHC(=O)) -
phenyl, (H2NC(=O)NHN=CH)-phenyl, 3-[(N-
methoxy)aminocarbonyl]-phenyl, 4-[(N-
methoxy)aminocarboxyl]-phenyl,
benzyloxyethoxyphenyl, (benzyl-
OCH2CH(Obenzyl)CH2O)-phenyl, (NH2C(=NH))phenyl,
(methylaminocarbonyl)phenyl, 3-formyl-phenyl,
3-(1-benzyloxyethyl)phenyl,
(methylaminocarbonyl) phenyl, (H2NC(=O)NH) -
phenyl, N-protected N-methylaminophenyl,
N-protected aminophenyl,
N,N-dimethylaminophenyl, 3-propionylphenyl,
(CH3NHC(=O)NH)-phenyl, 3-(2-imidazolyl-
C(=O))phenyl, 3-(CH3CH2C(=N-O-benzyl))phenyl,
N,N-dimethylglycylaminophenyl, 3-((N-
phenylmethoxycarbonylaminoglycyl)amino)phenyl,
3-((N-phenylmethoxycarbonylamino-L-
alanyl)amino)phenyl, 3-((N-
phenylmethoxycarbonylamino-L-
phenylalanyl)amino)phenyl, 3-(CF3CH2C(=N-
Obenzyl))phenyl, alanylaminophenyl,
phenylalanylaminophenyl, (methylsulfonyl)pentyl,
N-protected N-ethylaminocarbonylphenyl, 3-(N-
imidazolylmethyl)phenyl, 3-(2,2,2-trifluoro-1-
hydroxyethyl)phenyl,
- 99 -
N-diethylaminocarbonylphenyl, N-protected
N-propylaminocarbonylphenyl, pyridinylmethyl,
aminocarbonylphenyl, 3 - (H2NC(=NObenzyl) -4-
fluorophenyl, 3- (5-methyl-1,2,3-
oxadiazolyl)phenyl, 3- (H2NC(=NObenzyl) -4-
fluorophenyl, benzimidazolylmethyl,
benzotriazolylmethyl, indazolylmethyl,
N-protected 3-ethylamino-5-indazolylmethyl, or
3-amino-5-benzisoxazolylmethyl;
m and n are independently 1, 2 or 3;
X is chloro, bromo or iodo; and
R3 is a hydroYy protecting group.
5. A process of Claim 1 for preparing an
alkylating agent of formula (I) wherein:
Q is selected from:
phenyl substituted with 0-2 R31;
naphthyl substituted with 0-2 R31;
pyridyl substituted with 0-2 R31;
pyrimidyl substituted with 0-2 R31;
straight-chain or branched alkyl of 1-6 carbons,
substituted with 0-2 R31;
R31 at each occurence is independently selected from:
hydrogen, chloro, bromo, fluoro, alkyl of 1- 3
carbons, OR13, nitro, CF3, cyano or N(R13) (R14);
R13 and R14 are independently selected from hydrogen
or alkyl of 1- 6 carbon atoms;
- 100 -
R3 is a hydroxy protecting group; and
x is chloro, bromo or iodo;
m and n are independently 1, 2 or 3.
6. A process for preparing a hydroxy halide
alkylating agent or an organooxy halide alkylating
agent of formula (Ia):
<IMG>
(Ib)
wherein:
Q is phenyl, naphthyl, pyridyl, pyrimidyl or straight-
chain or branched alkyl of 1- 6 carbons;
X is chloro, bromo or iodo;
Y and Z are independently hydrogen, chloro, bromo,
fluoro, alkyl of 1-3 carbons, OR1A, nitro, CF3,
cyano or N(R1A) (RA); where
R1A and RA independently are hydrogen or alkyl of 1-6
carbon atoms;
R3 is a hydroxy protecting group; and
m and n are independently 1, 2 or 3;
comprising the steps of:
(1) reacting an organodiol of formula (IIb):
- 101 -
<IMG>
(IIb)
wherein Q, Y, Z, m and n are defined as for formula
(Ib), with a halogenating reagent in a chlorinated
organic solvent, with the proviso that the
halogenating reagent is not a hydrogen halide, to form
a compound of formula (IAb):
<IMG>
(IAb)
where Q, X, Y, Z, m and n are defined as for formula
(Ib); and
(2) reacting compound (IAb) with a reagent
suitable for protecting hydroxy groups to form the
compound of formula (Ib), where R3 is a hydroxy
protecting group.
7. A method for preparing a hydroxy halide
alkylating agent or an organooxy halide alkylating
agent comprising reacting an organodiol with a
halogenating reagent in a chlorinated organic solvent,
with the proviso that the halogenating reagent is not
a hydrogen halide.
8. A process of Claim 1 wherein R3 is selected
from: triphenylmethyl, tetrahydropyranyl,
-102-
tetrahydrofuranyl, t-butyl, methyl, methoxymethyl,
methylthiomethyl, benzyloxymethyl,
t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-
trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl,
trimethylsilyl, triethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, pivaloate,
or N-phenylcarbamate.
9. A process of Claim 1 wherein the compound of
formula (I) is obtained by carrying out steps (1) and
(2) without isolation of the compound of formula (IA).
10. A process of Claim 1 wherein the
halogenating reagent of step (1) is selected from:
thionyl halide, oxalyl halide, phosphorous
pentahalide, or phosphorous oxychloride.
11. A process of Claim 1 wherein the
halogenating reagent of step (1) is thionyl chloride.
12. A process of Claim 1 wherein the
chlorinated organic solvent is selected from:
chloroform, methylene chloride, tetrachloroethane,
butyl chloride, or dichloroethane.
13. A process of Claim 1 wherein the R3 is
triphenylmethyl and step (2) is carried out using
acid-catalyzed triphenylmethylation.
14. A process for alkylating a cyclic urea
compound of formula (IV):
- 103 -
<IMG>
(IV)
wherein:
R4 and R7 are independently selected from the
following groups:
hydrogen;
C1-C8 alkyl substituted with 0-3 R11;
C2-C8 alkenyl substituted with 0-3 R11;
C2-C8 alkynyl substituted with 0-3 R11;
a C3-C14 carbocyclic ring system substituted
with 0-3 R11 or 0-3 R12;
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-2 R12;
-OR13; -SR13;
R4A and R7A are independently selected from the
following groups:
hydrogen;
C1-C4 alkyl substituted with 0-3 C1-C2 benzyloxy;
benzyl substituted with 0-3 C1-C2 alkoxy;
-OR13; -SR13;
-104-
R4 and R4A can alternatively join to form a 5-7
membered carbocyclic ring substituted with 0-2 R12;
R7 and R7A can alternatively join to form a 5-7
membered carbocyclic ring substituted with 0-2 R12;
q is 0, 1, or 2;
R5 is selected from H; fluorine; C1-C6 alkyl
substituted with 0-3 R11; -N(R20)2; -SR20; or
-OR20, -N3;
R6 is independently selected from: hydrogen, fluorine,
C1-C6 alkyl substituted with 0-3 R11, -N(R20)2,
-SR20, or -OR21, -N3;
R5 and R6 can alternatively join to form an epoxide or
aziridine ring; a cyclic hydroxyl protecting
group; -OCH2SCH2O-; -OC(R1)(R2)O-; -OC(=S)O-;
-OC(=O)C(=O)O-; -OC(CH3)2O-;
-OC(OCH3) (CH2CH2CH3)O-; or any group that, when
administered to a mammalian subject, cleaves to
form a free dihydroxyl or diamino or hydroxyl
and amino;
R1 and R2 are independently H, C1-C4 alkyl, C1-C4
alkoxy, C6-C10 aryl, C7-C14 arylalkyl, C1-C4
haloalkyl, C3-C7 cycloalkyl, or alternately, R1
and R can be taken together with the carbon to
which they are attached to form a 3-7 membered
saturated carbocyclic ring system;
R20 and R21 are independently selected from:
-105-
hydrogen;
C1-C6 alkyl substituted with 0-3 R11;
C3-C6 alkoxyalkyl substituted with 0-3 R11;
C1-C6 alkylcarbonyl substituted with 0-3 R11;
C1-C6 alkoxycarbonyl substituted with 0-3 R11;
C1-C6 alkylaminocarbonyl substituted with 0-3
R11;
benzoyl substituted with 0-3 R12;
phenoxycarbonyl substituted with 0-3 R12;
phenylaminocarbonyl substituted with 0-3 R12; or
any group that, when administered to a mammalian
subject, cleaves to form a free hydroxyl, amino
or sulfhydryl;
R11 is selected from one or more of the following:
H, keto, cyano, -CH2NR13R14, -NR13R14, -OR13,
-SR13, -S(O)R13, -S(O)2R13, -NR14C(=O)R13,
=NOR14, -NR14C(=O)OR14, -OC(=O)NR13R14,
-NR13C(=O)NR13R14, -NR14SO2NR13R14, -NR14SO2R13,
-SO2NR13R14, -OP(O)(OR13)2, C1-C4 alkyl, C2-C4
alkenyl, C3-C6 cycloalkylmethyl, benzyl,
phenethyl, phenoxy, benzyloxy, nitro, C7-C10
arylalkyl, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl
substituted with -NR13R14, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkylcarbonyl, C1-C4 alkylcarbonylamino,
2-(1-morpholino)ethoxy, azido, or
-C(R14)=N(OR14);
1-3 amino acids linked together via amide bonds,
said amino acid being linked via the amine or
carboxylate terminus;
C3-C10 cycloalkyl substituted with 0-2 R12;
-106-
C1-C4 alkyl substitued with 0-2 R12
aryl(C1-C3 alkyl)-, substituted with 0-2 R12;
C2-C6 alkoxyalkyl-, substituted with 0-2 R12;
C1-C4 alkylcarbonyloxy substituted with 0-2 R12,
C6-C10 arylcarbonyloxy substituted with 0-2 R12,
a C5-C14 carbocyclic residue substituted with 0-
3 R12;
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-3 R12;
R11A is selected from one or more of the following:
H, keto, cyano, -CH2N(R13A)R(14A), -N(R13A)R(14A),
-CO2H, -OC(=O)(C1-C3 alkyl), -O-benzyl, C2-C6
alkoxyalkyl, -C(=O)NH2, -OC(=O)NH2, C1-C4 alkyl,
C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, benzyl, phenethyl, phenoxy,
benzyloxy, nitro, C7-C10 arylalkyl, C3-C6
cycloalkoxy, C1-C4 alkyl, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, C1-C4 alkylcarbonylamino,
2-(1-morpholino)ethoxy, azido, aryl(C1-C3 alkyl),
a C5-C14 carbocyclic residue; a 5- to 10-
membered heterocyclic ring system containing 1
to 4 heteroatoms independently selected from
-107-
oxygen, nitrogen or sulfur, said heterocyclic
ring system substituted with 0-3 R12A.
R12, when a substituent on carbon, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10
arylalkyl, C1-C4 alkoxy, sulfonamide, formyl, C3-C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkylene optionally
substituted with -Si(CH3)3, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, C1-C4 alkylcarbonylamino, -SR13,
-S(O)R13, -S(O)2R13, -SO2NR13R14, -NHSO2R14,
-OCH2CO2R13, 2-(1-morpholino)ethoxy,
-C(R14)=N(OR14); or
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected from
oxygen, nitrogen or sulfur;
or R12 may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5- or
6-membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons
with C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14; or, when R12 is attached to a saturated
carbon atom, it may be =O or =S; or when R12 is
attached to sulfur it may be =O;
R12, when a substituent on nitrogen, is selected from
one or more of the following:
-108-
phenyl, benzyl, phenethyl, benzyloxy, C1-C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4
alkylcarbonyl, -C(R14)=N(OR14);
R12A, when a substituent on carbon, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6
cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy,
sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C2-
C6 alkoxyalkyl optionally substituted with
-Si(CH3)3, C1-C4 benzyloxyalkyl, methylenedioxy,
ethylenedioxy, C1-C4 alkylcarbonyl, C1-C4
alkylcarbonylamino, -SMe, -S(O)Me, -S(O)2Me,
-OCH2CO2R13, 2-(1-morpholino)ethoxy; or
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected from
oxygen, nitrogen or sulfur;
or R12A may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5- or
6-membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons
with C1-C4 alkyl, C1-C4 alkoxy, benzyloxy; or, when
R12A is attached to a saturated carbon atom, it may
be =O or =S; or when R12 is attached to sulfur it
may be =O;
R12A, when a substituent on nitrogen, is selected from
one or more of the following:
-109-
phenyl, benzyl, phenethyl, benzyloxy, C1-C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6
alkoxyalkyl, C1-C4 alkylcarbonyl;
R13 is selected from:
phenyl substituted with 0-3 R11A;
benzyl substituted with 0-3 R11A;
C1-C6 alkyl substituted with 0-3 R11A;
C2-C4 alkenyl substituted with 0-3 R11A;
C1-C6 alkylcarbonyl substituted with 0-3 R11A;
C1-C6 alkoxycarbonyl substituted with 0-3 R11A;
C1-C6 alkylaminocarbonyl substituted with 0-3
R11A;
C3-C6 alkoxyalkyl substituted with 0-3 R11A;
an amine protecting group when R13 is bonded to
N;
a hydroxy protecting group when R13 is bonded to
O;
R14 is benzyloxy, C1-C6 alkyl substituted with 0-3
groups selected from -Obenzyl, C1-C4 alkoxy, C1-
C6 alkoxy, C2-C6 alkenyl, phenyl, benzyl, an
amine protecting group when R14 is bonded to N, a
hydroxy protecting group when R14 is bonded to O;
R13 and R14 can alternatively join to form -(CH2)4-,
-(CH2)5-, -CH2CH2N(R15)CH2CH2-, or
-CH2CH2OCH2CH2-;
R13A and R14A are independently selected from: H, C1-
C6 alkyl;
- 110 -
R13A and R14A can alternatively join to form -(CH2)4-,
-(CH2)5-, -CH2CH2N(R15)CH2CH2-, or
-CH2CH2OCH2CH2 -;
R15 is H or CH3;
said process comprising the steps of:
(1) reacting an organodiol of formula (II):
<IMG>
(II)
wherein Q, m and n are defined as above, with a
halogenating reagent in a chlorinated organic solvent,
with the proviso that the halogenating reagent is not
a hydrogen halide, to form a compound of formula (IA)
<IMG>
(IA)
where Q, X, m and n are defined as above; and
(2) reacting compound (IA) with a reagent
suitable for the protection of hydroxy groups to form
the compound of formula (I) where R3 is a hydroxy
protecting group; and
(3) reacting compound (I) with the compound of
formula (IV) to form a compound of formula (V):
- 111 -
<IMG>
(V)
wherein R3, R4, R4A, R5, R6, R7, R7A, m, n and q are
as defined above.
15. A process of Claim 14 wherein:
q is 0, 1, or 2;
m and n are independently 1, 2 or 3;
X is chloro, bromo or iodo;
R3 is a hydroxy protecting group;
R4 and R7 are independently selected from the
following groups:
hydrogen;
C1-C8 alkyl substituted with 0-3 R11;
C2-C8 alkenyl substituted with 0-3 R11;
C2-C8 alkynyl substituted with 0-3 R11;
R4A and R7A are hydrogen;
-112-
R5 is selected from fluorine, -N(R20)2, or -OR20;
R6 is independently selected from: hydrogen, fluorine,
-OR21;
R5 and R6 can alternatively join to form an epoxide or
aziridine ring; -OCH2SCH2O-; -OCH2O-; -OC(=S)O-;
-OC(=O)C(=O)O-; -OC(R1)(R2)O-;
-OC(OCH3)(CH2CH2CH3)O-; or any group that, when
administered to a mammalian subject, cleaves to
form a free dihydroxyl or diamino or hydroxyl
and amino;
R1 and R2 are independently H, C1-C4 alkyl, or,
alternately, R1 and R2 can be taken together with
the carbon to which they are attached to form a
5-6 membered saturated carbocyclic ring system;
R20 and R21 are independently selected from:
hydrogen;
C1-C6 alkylcarbonyl substituted with 0-3 R11;
C1-C6 alkoxycarbonyl substituted with 0-3 R11;
benzoyl; or any group that, when administered to
a mammalian subject, cleaves to form a free
hydroxyl;
R11 is selected from one or more of the following:
H, keto, cyano, -CH2NR13R14, -NR13R14, -OR13,
-S(O)pR13, C1-C4 alkyl, C2-C4 alkenyl, C3-C10
cycloalkyl substituted with 0-2 R12, a C5-C14
carbocyclic residue substituted with 0-3 R12,
- 113 -
aryl(C1-C3 alkyl)-, substituted with 0-2 R12,
aryl substituted with 0-3 R12; or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-3 R12;
R12, when a substituent on carbon, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10
arylalkyl, C1-C4 alkoxy, sulfonamide, formyl, C3-C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkylene optionally
substituted with -Si(CH3)3, C1-C4 benzyloxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, C1-C4 alkylcarbonylamino,
-S(O)pR13, -SO2NR13R14, -NHSO2R14,
2-(1-morpholino)ethoxy, -C(R14)=N(OR14); or
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected from
oxygen, nitrogen or sulfur;
or R12 may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5- or
6-membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons
with C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-114-
-NR13R14; or, when R12 is attached to a saturated
carbon atom, it may be =O or =S; or when R12 is
attached to sulfur it may be =O;
R12, when a substituent on nitrogen, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, benzyloxy, C1-C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4
alkylcarbonyl, -C(R14)=N(OR14);
R13 is C1-C6 alkyl; C3-C6 alkoxyalkyl; C2-C4 alkenyl;
phenyl; or benzyl;
R14 is benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6
alkenyl, phenyl, benzyl, an amine protecting
group when R14 is bonded to N, or a hydroxy
protecting group when R14 is bonded to O;
R15 is H or CH3;
p is 0, 1 or 2;
Q is independently selected at each occurrence from
the following:
C1-C8 alkyl substituted with 0-3 R31;
C2-C8 alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
a C3-C14 carbocyclic ring system substituted
with 0-5 R31 or 0-5 R32;
R31 is selected from one or more of the following:
- 115 -
cyano, -CH2NR13R14, -NR13R14, -OR13, C2-C6
alkoxyalkyl, -S(O)pR13, C1-C4 alkyl, C2-C4
alkenyl, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, benzyl, phenethyl, phenoxy,
benzyloxy, nitro, C7-C10 arylalkyl, formyl, C3-C6
cycloalkoxy, C1-C4 alkyl substituted with
-NR13R14, C1-C4 alkoxycarbonyl, C1-C4
alkylcarbonyloxy, C1-C4 alkylcarbonyl,
-OCH2CO2R13, 2-(1-morpholino)ethoxy, azido,
-C(R14)=N(OR14); or
a C5-C14 carbocyclic residue substituted with 0-
5 R32; or
aryl substituted with 0-3 R32; or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-2 R32;
R32, when a substituent on carbon, is selected from
one or more of the following:
phenethyl, phenoxy, C3-C10 cycloalkyl, C3-C6
cycloalkylmethyl, C7-C10 arylalkyl, benzyl
protected oxime, C2-C6 alkoxyalkyl,
methylenedioxy, ethylenedioxy, C1-C4
alkylcarbonyloxy, -NHSO2R14,
benzyloxy, 2-(1-morpholino)ethoxy, -CONR13NR13R14,
cyano, sulfonamide, C3-C6 cycloalkoxy, -NR13R14,
-C(R14)=N(OR14), -NO2, -OR13, -NR40R41, -SOpR13,
-SOpNR13R14, -C(=O)NR13R14, -OC(=O)NR13R14,
- 116 -
-C(=O)R11, phenyl, -C(=O)NR13-(C1-C4 alkyl)-
NR13R14, -C(=O)NR40R41,
-C(=O)NR13C(R11)2NR13R14;
-C(=O)NR13C(R11)2NR13CO2R13;
-C(=O)NR13-(C1-C4 alkyl)-NR13CO2R13;
-C(=O)N(R13)-(C1-C4 alkyl)-R11; or
-C(=O)C(R11)2NR13R14;
-C(=O)C(R11)2NR13CO2R13; -C(=O)-(C1-C4 alkyl)-
NR13R14; -C(=O)-(C1-C4 alkyl)-NR13CO2R13; or
C1-C4 alkoxy substituted with 0-4 groups selected
from: R11, C3-C6 cycloalkyl, -CO2R13,
-C(=O)NR13R14, -NR13R14 or benzyloxy;
C1-C4 alkyl substituted with 0-4 groups selected
from: R11, =NR14, =NNR13C(=O)NR13R14, or -NR13R14;
C2-C4 alkenyl substituted with 0-4 R11;
C2-C4 alkynyl substituted with 0-4 R11;
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected
from oxygen, nitrogen or sulfur, substituted with
0-2 R12;
or R32 may be a 3- or 4- carbon chain attached to
adjacent carbons on the ring to form a fused 5- or
6-membered ring, said 5- or 6- membered ring being
optionally substituted on the aliphatic carbons
with halogen, C1-C4 alkyl, C1-C4 alkoxy,
benzyloxy, or -NR13R14; or, when R32 is attached
to a saturated carbon atom, it may be =O, =S, =NO-
-117-
benzyl; or when R32 attached to sulfur it may be
=O;
R40 is selected from: H, C1-C3 alkyl;
R41 is selected from:
-C(=O)NR13R14;
-C(=O)NR13NR13R14;
-C(=O)C(R11)2NR13R14;
-C(=O)C(R11)2NR13NR13R14;
-C(=O)C(R11)2NR13CO2R13;
-C(=O)H;
-C(=O)R11;
-C(=O)-(C1-C4 alkyl)-NR13R14;
-C(=O)-(C1-C4 alkyl)-NR13CO2R13;
1-3 amino acids linked together via amide bonds,
and linked to the N atom via the carboxylate
terminus;
16. A process of Claim 14 for alkylating
compounds of the formula (IV) wherein:
q is 1;
m and n are independently 1, 2 or 3;
X is chloro, bromo or iodo;
R3 is a hydroxy protecting group;
R4 and R7 are independently selected from: benzyl,
fluorobenzyl, pyrrolylmethyl, methoxybenzyl,
isobutyl, nitrobenzyl, N-protected aminobenzyl,
- 118 -
thienylmethyl, O-protected hydroxybenzyl,
pyridylmethyl, or naphthylmethyl;
R4A and R7A are hydrogen;
R5 is -OR20;
R6 is -OR21;
R5 and R6 can alternatively join to form an
-OCH2SCH2O-; -OCH2O-; -OC(=S)O-; -OC(=O)C(=O)O-;
-OC(CH3)2O-; -OC(OCH3)(CH2CH2CH3)O-; or any group
that, when administered to a mammalian subject,
cleaves to form a free dihydroxyl or hydroxyl;
R20 and R21 are independently selected from:
hydrogen;
C1-C6 alkylcarbonyl substituted with 0-3 R11;
C1-C6 alkoxycarbonyl substituted with 0-3 R11;
benzoyl; or any group that, when administered to
a mammalian subject, cleaves to form a free
hydroxyl,
R11 is selected from one or more of the following:
H, keto, cyano, -CH2NR13R14, -NR13R14, -OR13,
-S(O)pR13, C1-C4 alkyl, C2-C4 alkenyl, C3-C10
cycloalkyl substituted with 0-2 R12, a C5-C14
carbocyclic residue substituted with 0-3 R12,
aryl (C1-C3 alkyl)-, substituted with 0-2 R12,
aryl substituted with 0-3 R12; or
a 5- to 10-membered heterocyclic ring system
containing 1 to 4 heteroatoms independently
- 119 -
selected from oxygen, nitrogen or sulfur, said
heterocyclic ring system being substituted with
0-3 R12;
R12, when a substituent on carbon, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10
arylalkyl, C1-C4 alkoxy, sulfonamide, formyl, C3-
C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted
with -NR13R14, -NR13R14, C2-C6 alkoxyalkylene
optionally substituted with -Si(CH3)3, C1-C4
benzyloxyalkyl, methylenedioxy, ethylenedioxy,
C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy,
C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino,
-S(O)pR13, SO2NR13R14, -NHSO2R14,
2-(1-morpholino)ethoxy, -C(R14)=N(OR14); or
a 5- or 6-membered heterocyclic ring containing
from 1 to 4 heteroatoms independently selected
from oxygen, nitrogen or sulfur;
or R12 may be a 3- or 4- carbon chain attached
to adjacent carbons on the ring to form a fused
5- or 6-membered ring, said 5- or 6- membered
ring being optionally substituted on the
aliphatic carbons with C1-C4 alkyl, C1-C4
alkoxy, hydroxy, or
-NR13R14; or, when R12 is attached to a
saturated carbon atom, it may be =O or =S; or
when R12 is attached to sulfur it may be =O;
-120-
R12, when a substituent on nitrogen, is selected from
one or more of the following:
phenyl, benzyl, phenethyl, benzyloxy, C1-C4
benzyloxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4
alkylcarbonyl, -C(R14)=N(OR14);
R13 is C1-C6 alkyl; C3-C6 alkoxyalkyl; C2-C4 alkenyl;
phenyl; or benzyl;
R14 is benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6
alkenyl, phenyl, benzyl, an amine protecting
group when R14 is bonded to N, or a hydroxy
protecting group when R14 is bonded to O;
R15 is H or CH3;
p is 0, 1 or 2;
Q is independently selected at each occurence from
the following:
allyl, methtyl, ethyl, propyl, cyclopropylmethyl,
n-butyl, i-butyl, CH2CH=C(CH3)2,
pyridinylmethyl, methallyl, n-pentyl, i-pentyl,
hexyl, phenyl, isoprenyl, propargyl, picolinyl,
methoxyethyl, cyclohexylmethyl, dimethyl-butyl,
ethoxyethyl, methyl-oxazolinylmethyl,
naphthylmethyl, methyloxazolinylmethyl,
vinyloxyethyl, pentafluorophenyl,
quinolinylmethyl, carboxyphenyl,
benzyloxyphenyl, phenylphenyl,adamantylethyl,
cyclopropylmethoxyphenyl, methoxyphenyl,
-121-
methylphenyl, ethoxyphenyl, benzyloxyphenyl,
benzyloxymethylphenyl, N-protected aminophenyl,
formylphenyl, cyanophenyl, cinnamyl,
allyloxyphenyl, fluorophenyl, difluorophenyl,
fluoromethylphenyl, cyclobutylmethyl,
cyclopentylmethyl, nitrophenyl, (H2NC(=O))-
phenyl, carbomethoxyphenyl, carboethoxyphenyl,
tetrazolylphenyl, and dimethylallyl, N-protected
aminomethylphenyl, (O-benzyl-
formaldoxime)phenyl, (O-methyl-
formaldoxime)phenyl, (CH3O2CO)-phenyl, (benzyl-
OCH2CH2N=CH)-phenyl,
N-benzylaminocarbonylphenyl, N-protected N-
methylaminophenyl, N-protected
N-ethylaminophenyl, N-protected
N-ethylaminomethylphenyl, acetylphenyl,
acetoxyphenyl, N-benzyloxylaminophenyl,
N-benzyloxylaminomethylphenyl,
(benzyloxyl)ethylphenyl, (CH3C(=NO-benzyl))-
phenyl, (H2NNHC(=O))-phenyl, (H2NC(=O)NHN=CH)-
phenyl, (CH3ONHC(=O))-phenyl, (HONHC(=O))-
phenyl, (CH3NHC(=O))-phenyl,
N,N-dimethylaminocarbonylphenyl, (benzyl-
OCH2CH(OH)CH2O)-phenyl, benzyloxyethoxybenzyl
(oxazolidinyl)-phenyl, (benzyloxyl)hexyl,
hexenyl, (benzyloxy)octyl, (benzyloxyl)pentyl,
(carboxy)pentyl, (carbomethoxy)pentyl,
(methylthio)phenyl, (methylsulfonyl)phenyl,
N,N-dimethylaminomethylphenyl, N-protected
N-methylaminomethylphenyl, glycylaminophenyl,
N,N-dimethylglycylaminophenyl,
alanylaminophenyl, (N-
phenylmethoxycarbonyl)alanylaminophenyl,
phenylalanylaminophenyl, (N-
phenylmethoxycarbonyl) phenylalanylaminophenyl,
- 122 -
(CH3CH2NHC(=O))-phenyl, N,N-
diethylaminocarbonylphenyl,
N-ethylaminocarbonylphenyl,
N-propylaminocarbonylphenyl,
N,N-diisopropylaminocarbonylphenyl, N,N-di-n-
propylaminocarbonylphenyl,
(benzyloxypropynyl)phenyl, (imidazolyl-C(=O))-
phenyl, (pyrazolyl-C(=O))-phenyl,
(pyridylmethylaminocarbonyl)phenyl,
(oxadiazolidinonyl)phenyl,
trifluoroacetylphenyl, (pyrazolyl)phenyl,
(H2NSO2)-phenyl, dibenzyloxyethylphenyl,
(MeHNC(=O)NH)-phenyl, (H2NC(=O)NH)-phenyl,
(HC(=O)NH)-phenyl, methanesulfonylpentyl,
methoxypentyl, N-formyl-N-methylaminophenyl,
acetylaminophenyl, propionylphenyl,
butyrylphenyl, (CH3CH2C(=NObenzyl))-phenyl,
(trifluorohydroxyethyl)phenyl, (CF3C(=NOH))-
phenyl, (N-methylglycyl)aminophenyl,
((4-morpholino)ethyl)aminocarbonylphenyl,
(N,N-dimethylaminoethyl)aminocarbonylphenyl,
(N,N-diethylaminoethyl)aminocarbonylphenyl,
(4-methylpiperazin-1-
ylethyl)aminocarbonylphenyl, (benzyl-
NHC(=O)O)phenyl, (CH3NHC(=O)O)phenyl,
(NH2C(=O)CH2O)phenyl, (NH2C(=NH))phenyl,
((N-phenylmethoxycarbonyl)glycylamino)phenyl,
(imidazolylmethyl)phenyl, ((CH3)3C-C(=O))phenyl,
(N-methyl-N-ethylaminoethyl)aminocarbonylphenyl,
(pyrrolidinylethyl)aminocarbonylphenyl,
(piperidinylethyl)aminocarbonylphenyl,
(H2NC(=NObenzyl))phenyl,
(H2NC(=NObenzyl))fluorophenyl,
benzimidazolylmethyl, benzotriazolylmethyl,
indazolylmethyl, benzoxazolinylmethyl,
- 123 -
benzisoxazolylmethyl, thienylmethyl, or
furylmethyl.
17. A process of Claim 14 for alkylating
compounds of formula (IV) wherein:
q is 1;
m and n are independently 1, 2 or 3;
X is chloro, bromo or iodo;
R3 is a hydroxy protecting group;
R4 and R7 are independently selected from: benzyl,
fluorobenzyl, pyrrolylmethyl, methoxybenzyl,
isobutyl, nitrobenzyl, N-protected aminobenzyl,
thienylmethyl, O-protected hydroxybenzyl,
pyridylmethyl, or naphthylmethyl;
R4A and R7A are hydrogen;
R5 and R6 join to form -OC(CH3)2O-;
Q is independently selected at each occurrence from
the following:
allyl, propyl, cyclopropylmethyl, n-hexyl, n-
butyl, CH2CH=C(CH3)2, methallyl, i-pentyl,
phenyl, hexyl, isoprenyl, cinnamyl,
fluorophenyl, (methylsulfonyl)phenyl,
cyclopropylmethyl, naphthylmethyl, 4-
pyridinylmethyl, benzyloxyhexyl, 2-
pyridinylmethyl, carboxypentyl,
cyclopentylmethyl, cyanophenyl,
- 124 -
quinolinylmethyl, vinylphenyl, benzyloxyphenyl,
benzyloxyphenyl, benzyloxypentyl,
(benzyloxyl)methylphenyl, carbomethoxyphenyl,
formylphenyl, (O-benzyl-formaldoxime)phenyl,
cyclobutylmethyl, difluorophenyl, nitrophenyl,
N-protected aminomethylphenyl, 3-(NHCHO)phenyl,
dibenzyloxyphenyl,
N-benzyloxylaminomethylphenyl, 3-(CH3OC(=O)O-
)phenyl, 3-(1-benzyloxyethyl)phenyl, 3-
(HOCH2CH2N=CH)phenyl, 3-(2-oxazolidinyl)phenyl,
3-(C6H5CH2NHC(=O)O)phenyl, 3-
(CH3NHC(=O)O)phenyl, acetylphenyl, (CH3C(=NO-
benzyl))-phenyl, 2-(hydroxymethyl)-
cyclopropylmethyl, (H2NNHC(=O))-phenyl,
(H2NC(=O)NHN=CH)-phenyl, 3-[(N-
methoxy)aminocarbonyl]-phenyl, 4-[(N-
methoxy)aminocarbonyl]-phenyl,
benzyloxyethoxyphenyl, (benzyl-
OCH2CH(Obenzyl)CH2O)-phenyl, (NH2C(=NH))phenyl,
(methylaminocarbonyl)phenyl, 3-formyl-4-
benzyloxyphenyl, 3-(1,2-dibenzyloxyethyl)phenyl,
(methylaminocarbonyl)phenyl, (H2NC(=O)NH)-
phenyl, N-protected N-methylaminophenyl, N-
protected aminophenyl, N,N-dimethylaminophenyl,
3-propionylphenyl, (CH3NHC(=O)NH)-phenyl, 3-(2-
imidazolyl-C(=O))phenyl, 3-(CH3CH2C(=N-
Obenzyl))phenyl, N,N-dimethylglycylaminophenyl,
3-((N-
phenylmethoxycarbonylaminoglycyl)amino)phenyl,
3-((N-phenylmethoxycarbonylamino-L-
alanyl)amino)phenyl, 3-((N-
phenylmethoxycarbonylamino-L-
phenylalanyl)amino)phenyl, 3-(CF3CH2C(=N-
Obenzyl))phenyl, alanylaminophenyl,
phenylalanylaminophenyl, (methylsulfonyl)pentyl,
- 125 -
N-protected N-ethylaminocarbonylphenyl, 3-(N-
imidazolylmethyl)phenyl, 3-(2,2,2-trifluoro-1-
hydroxyethyl)phenyl,
N-diethylaminocarbonylphenyl, N-protected
N-propylaminocarbonylphenyl, pyridinylmethyl,
aminocarbonylphenyl, 3-(H2NC(=NObenzyl)-4-
fluorophenyl, 3-(5-methyl-1,2,3-
oxadiazolyl)phenyl, 3-(H2NC(=NObenzyl)-4-
fluorophenyl, benzimidazolylmethyl,
benzotriazolylmethyl, indazolylmethyl, N-
protected 3-ethylamino-5-indazolylmethyl, or 3-
amino-5-benzisoxazolylmethyl.
18. A process of Claim 14 wherein:
q is 1;
R4 and R7 are independently selected from: benzyl,
fluorobenzyl, pyrrolylmethyl, methoxybenzyl,
isobutyl, nitrobenzyl, N-protected aminobenzyl,
thienylmethyl, O-protected hydroxybenzyl,
pyridylmethyl, or naphthylmethyl;
R4A and R7A are H;
R5 and R6 join to form -OC(CH3)2O-;
Q is selected from:
phenyl substituted with 0-2 R31;
naphthyl substituted with 0-2 R31;
pyridyl substituted with 0-2 R31;
pyrimidyl substituted with 0-2 R31;
straight-chain or branched alkyl of 1-6 carbons,
substituted with 0-2 R31;
- 126 -
R31 at each occurence is independently selected from:
hydrogen, chloro, bromo, fluoro, alkyl of 1-3
carbons, OR13, nitro, CF3, cyano or N(R13)(R14);
R13 and R14 are independently selected from hydrogen
or alkyl of 1-6 carbon atoms;
R3 is a hydroxy protecting group; and
X is chloro, bromo or iodo;
m and n are independently 1, 2 or 3.
19. A process of Claim 14 wherein R3 is
selected from: triphenylmethyl, tetrahydropyranyl,
tetrahydrofuranyl, t-butyl, methyl, methoxymethyl,
methylthiomethyl, benzyloxymethyl,
t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-
trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,
trimethylsilyl, triethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, pivaloate,
or N-phenylcarbamate.
20. A process of Claim 14 wherein the compound
of formula (I) is obtained by carrying out steps (1)
and (2) without isolation of the compound of formula
(IA).
21. A process of Claim 14 wherein the
halogenating reagent of step (1) is selected from:
thionyl halide, oxalyl halide, phosphorous
pentahalide, or phosphorous oxychloride.
22. A process of Claim 14 wherein the
halogenating reagent of step (1) is thionyl chloride.
- 127 -
23. A process of Claim 14 wherein the
chlorinated organic solvent is selected from:
chloroform, methylene chloride, tetrachloroethane,
butyl chloride, or dichloroethane.
24. A process of Claim 14 wherein the R3 is
triphenylmethyl and step (2) is carried out using
acid-catalyzed triphenylmethylation.
25. A process of Claim 14 wherein step (3) is
carried out in the presence of a suitable base.
26. A process for alkylating a cylic urea
compound of formula (IVb):
<IMG>
(IVb)
wherein:
R4 and R7 are independently benzyl, fluorobenzyl,
pyrrolylmethyl, methoxybenzyl, isobutyl,
nitrobenzyl, N-protected aminobenzyl,
thienylmethyl, O-protected hydroxybenzyl,
pyridylmethyl, or naphthylmethyl;
R5 and R6 are independently hydrogen or -OR or,
alternatively, R5 and R6 may join to form
-OC(CH3)2O-;
R is a hydroxy protecting group; and
q is 0, 1 or 2;
-128-
comprising the steps of:
(1) reacting an organodiol of formula (IIb):
<IMG>
(IIb)
wherein:
Q is phenyl, naphthyl, pyridyl, pyrimidyl or
straight-chain or branched alkyl of 1-6
carbons;
Y and Z are independently hydrogen, chloro, bromo,
fluoro, alkyl of 1-3 carbons, OR1A, nitro, CF3,
cyano or N(R1A)(R2A); where
R1A and R2A independently are hydrogen or alkyl of
1-6 carbon atoms; and
m and n are independently 1, 2 or 3;
with a halogenating reagent in a chlorinated organic
solvent, with the proviso that the halogenating
reagent is not a hydrogen halide, to form a compound
of formula (IAb);
<IMG>
(IAb)
wherein:
Q, Y, Z, m, and n are as defined above; and
- 129 -
X is chloro, bromo or iodo;
(2) reacting compound (IAb) with a reagent
suitable for the protection of hydroxy groups to form
the compound of formula (Ib) where R3 is a hydroxy
protecting group; and
(3) reacting compound (IVb) with compound (Ib)
to form a compound of formula (Vb):
<IMG>
(Vb)
wherein R3, R4, R5, R6, R7, Q, Y, Z, m, n and q are as
defined above.
- 130 -
